Optimal Dose of Anti-lymphocyte Globulin in Kidney Transplant Recipients With Low Immunological Risk

Summary

Antithymocyte globulins (ATG) are the gold standard of induction therapies and are currently used to prevent or treat acute rejection in solid organ transplantation. They induce rapid depletion of immune cells, particularly T lymphocytes. The time to immune reconstitution after ATG is characterized by significant intra- and inter-individual variability in reconstitution of immune cell subpopulations (T and B cells, NK cells, dendritic cells). This variability explains the prolonged T cell lymphopenia observed in some patients, which is a surrogate immune biomarker associated with an increased risk of death after 2 years of renal transplantation and more infections, cancers and atheromatous events. However, ATG also promotes an increase in the proportion of Treg cells. Although the underlying mechanisms are still debated, data from experimental animal models confirm the tolerogenic properties of ATG. ATGs are associated with improved allograft survival without rejection in patients at high immunological risk and are therefore indicated as first-line therapy in this population. In patients at low immunological risk, anti-CD25 monoclonal antibodies (anti-CD25mAb) are recommended as first-line therapy because ATGs are associated with a higher incidence of infections despite their equivalent efficacy in this population compared to anti-CD25mAb. However, neither the dosages nor the treatment duration of ATGs are clearly defined (recommended Grafalon® dosages range from 5 to 2 mg/kg/day for 5 to 21 days) and ATGs remain widely prescribed to allow early withdrawal of corticosteroids. Determination of optimal non-depleting doses of ATG could be of great interest because, in vitro, ATG is able to induce regulatory polarization of naïve T cells even at non-depleting doses. Thus, the use of such doses in patients with low immunological risk may be of interest in clinical practice with respect to anti-CD25mAb, particularly for their pro-regulatory properties and their low cost. This question must be clearly addressed in a pilot clinical study.

The purpose of this study is to find the optimal non-depleting dose (Maximum Tolerated Dose; MTD) of rabbit anti-human T-lymphocyte immunoglobulin (Grafalon®) to prevent the complications associated with prolonged CD4 T cell lymphopenia in low immunological risk renal transplant recipients. The primary outcome for the de-escalation study is the Dose Limiting Toxicity (DLT) defined by a T cell (CD3+) relative depletion above 30 % compared to baseline (Day 0) at the end of the Grafalon® induction treatment (Day 4).

The patients under study are adult receiving first kidney transplantation without a high immunological risk of rejection (african-American ethnicity, presence of a donor-specific antibody, blood group incompatibility, delayed onset of graft function (i.e donor after cardiac death), cold ischemia time \>24 hours, anti-HLA immunization (Flow PRA \> or = 20%, presence of donor specific antibody before and/or at time of transplantation and with a positive CDC and FXM with historical and/or transplant day sera), bacterial, viral or mycotic and parasitic infections, history of opportunistic infection that required intensive care hospitalization in the two years preceding the transplant, related donor with two-haplotype HLA matched kidneys, multi-organ transplant, history of cancer, thrombocytopenia \< 50 000 platelets/µl, hypersensitivity to the active substance or to the excipients of Grafalon (monosodium phosphate dihydrate, phosphoric acid).

The inclusion period is one year. According to the active file of the center of Besançon, it is planned to include 2 patients per month. The maximum number of patients to include is 18. With a margin of error of 20%, it is possible to include all patients in 1 year. The duration of patient participation in the study is 1 year (one-year follow-up). Consequently, the duration of the study is estimated at 2 years (1 year of inclusion and 1 year of follow-up).

ODORAT is a monocenter, open-label, de-escalation phase1b controlled study. The study will be proposed to patients receiving a first kidney transplant and matching the criteria of inclusion. Recruitment will be achieved only in Besançon's transplant unit. The physician gives information on the study and collect informed consent. Then the treatment is assigned according to the dose determined by the dose de-escalation study. The first dose tested is the dose level at 2 mg/kg/day (level 3). This dose is the reference dose according to the current recommendations. The number of patients included at each dose is determined according to Bayesian optimal interval (BOIN) design.

The administration of treatment begin at time of transplantation according to recommendation.

The study will include 11 visits: D0 (baseline) to D4 (primary end point assessement), D7, D14, M1, M3, M6 and M12, to analyze pharmacokinetics of Grafalon and the immune phenotype.

Conditions

• Renal Transplantation

Interventions

DRUG

Grafalon® administered during 5 consecutive days at 2 mg/kg/j

This de-escalation study was planned to investigate 3 doses level of Grafalon® administered during 5 consecutive days, i.e.: Group 3 : 2 mg/kg/j, Group 2 : 1 mg/kg/j, Group 1 : 0,5 mg/kg/j. Group 3 receives treatment in accordance with health recommendations as part of prophylactic treatment for acute rejection after allogeneic solid organ transplantation, at the minimum dose, i.e., 2 to 5 mg/kg/day for 5 to 21 days.

DRUG

Grafalon® administered during 5 consecutive days at 1 mg/kg/j

This de-escalation study was planned to investigate 3 doses level of Grafalon® administered during 5 consecutive days, i.e.: Group 3 : 2 mg/kg/j, Group 2 : 1 mg/kg/j, Group 1 : 0,5 mg/kg/j. Group 2 receive treatment at lower doses than the recommended dose for the same duration (5 days). Treatment begins on the day of transplantation immediately before the procedure at induction of sedation.

DRUG

Grafalon® administered during 5 consecutive days at 0,5 mg/kg/j

This de-escalation study was planned to investigate 3 doses level of Grafalon® administered during 5 consecutive days, i.e.: Group 3 : 2 mg/kg/j, Group 2 : 1 mg/kg/j, Group 1 : 0,5 mg/kg/j. Group 1 receive treatment at lower doses than the recommended dose for the same duration (5 days). Treatment begins on the day of transplantation immediately before the procedure at induction of sedation

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Besancon

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-01-15

Primary Completion

2026-01-20

Completion

2027-01-15